Trimethylsilyl‐Protected Alkynes as Selective Cross‐Coupling Partners in Titanium‐Catalyzed [2+2+1] Pyrrole Synthesis

Abstract

Trimethylsilyl (TMS)-protected alkynes serve as selective alkyne cross coupling partners in Ti-catalyzed [2+2+1] pyrrole synthesis. Reactions of TMS-protected alkynes with internal alkynes and azobenzene catalyzed by Ti imido catalysts yield pentasubstituted 2-TMS-pyrroles with greater than 90% selectivity over the other 9 possible pyrrole products. The steric and electronic effects of the TMS group have both been identified to play key roles in this highly selective pyrrole synthesis. This strategy provides a convenient methodology to synthesize multisubstituted pyrroles as well as an entrypoint into further pyrrole diversification through facile modification of the resulting 2-silylpyrrole products, as demonstrated through a short formal synthesis of the marine natural product Lamellarin R.

Synthesis of pentasubstituted 2-aryl pyrroles from boryl and stannyl alkynes via one-pot sequential Ti-catalyzed [2 + 2 + 1] pyrrole synthesis/cross coupling reactions

“…First, several potential heteroatom-substituted alkynes were examined as candidates for the [2 + 2 + 1] reaction, focusing on heteroatomic groups that could later be good transmetallation partners in cross-coupling catalysis ( Table 1). The functional groups involved in the initial screen included boronic acid pinacol ester ( Initial reaction conditions were based off from previously successful conditions for TMS-substituted alkyne substrates, 13 using chloride-based Ti catalysts that are typically most robust for [2 + 2 + 1] reactions. 22,23 All new heteroatom-substituted reactions resulted in signicantly lower yields than the corresponding TMS-substituted alkyne reactions, highlighting the challenges of conserving a reactive transmetallating agent through another organometallic transformation.…”

“…[32][33][34] In the case of 9-BBN, polarization is a result of the B mesomeric effect, 26 while for SnMe 3 polarization results from hyperconjugation between s Sn-R and p * CÀC in a manner similar to TMS-protected alkynes. 13 [PhCCCu] n (1a-Cu) exhibited excellent regioselectivity for the formation of 3a-Cu (Table 1, entry 4; Fig. S10 †); however, the yield and overall chemoselectivity for the heterocoupled product was very low owing to the insolubility of polymeric 1a- Cu.…”

“…12 Chemo-and regioselective intermolecular reactions can be achieved via the heterocoupling of trialkylsilyl-protected alkynes, which selectively engage in migratory insertion into a key azatitanacyclobutene [2 + 2] cycloadduct intermediate. 13 (Fig. 1, top).…”

Synthesis of Pentasubstituted 2-Aryl Pyrroles from Boryl and Stannyl Alkynes via One-Pot Sequential Ti-Catalyzed [2+2+1] Pyrrole Synthesis/Cross Coupling Reactions

“…Although nitro groups and esters are commonly tolerated in Suzuki reactions, 11 B NMR spectroscopic evidence indicates that deleterious chemistry with the 9-BBN group may be taking place ( Figure S150). Finally, given that 9-BBN and Sn alkynes undergo coupling with similar chemo-and regioselectivity to TMS-protected alkynes, 33 intramolecular competition experiments were conducted to determine the relative directing ability of the two functional groups compared to TMS ( Figure 5). There are few points of comparison for the regioselectivity of insertion into these types of doubly-functionalized alkynes.…”

Efficient Synthesis of Polysubstituted Pyrroles Based on [3+2] Cycloaddition Strategy Utilizing [1,2]‐Phospha‐Brook Rearrangement under Brønsted Base Catalysis

“…There are numerous synthetic methods of pyrroles including classical reactions, such as the Knorr reaction, Hantzsch reaction, and Paal-Knorr condensation reaction, and new reactions are emerging continuouslyb ased on av ariety of strategies. [3,4] Amongt hem, the [3+ +2] cycloaddition is a powerful strategy in which ap yrrole framework is constructed from two or more components in ac onvergent fashion. Such convergent methodologies are attractive particularly from the view point of the librarys ynthesis of analogues having av ariety of substituents.…”